Updates on Tinea Incognita: Literature review

Background and Purpose: Tinea incognita (TI), or the other equivalent tinea atypica, is a term used to declare the atypical presentation of dermatophyte infections caused by the administration of steroids or other immunosuppressive medications which modulate the local and systemic immune response. It can mimic other dermatoses; hence making diagnostic challenges for dermatologists. Tina incognita may be misdiagnosed as many dermatoses. Based on previous studies, corticosteroids may cause different clinical manifestations of dermatophytes that might be very different from those that are commonly described. Materials and Methods: This narrative review was conducted using PubMed and Scopus databases. Search terms included “Tinea incognita” and “Atypical dermatophytosis”. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, reviews, and case reports. The search was restricted to articles written in the English language from 2006 to Feb 01, 2023. Moreover, duplicate articles and non-available full-text articles were excluded. The extracted data of the search results were retrieved in this study. The morphological patterns, prevalence, sight of infection, and causative agents were also described. Results: Prevalence of different patterns of TI were recorded as 50% (431 out of 862 cases) for eczema-like lesions followed by psoriasis-like and 6.61% (57 out of 862) for parapsoriasis-like pattern. Moreover, each of the rosacea-like and pyoderma-like lesions equally accounted for 4.98 % of cases (43 out of 862). In addition, the prevalence of causative agents was reported as follows: Trichophyton rubrum accounted for 247 isolates (40%) as the most prevalent, followed by Trichophyton mentagrophytes (n=152, 24%) and Microsporum canis (n=119, 19%). Conclusion: Tinea incognita is a great mimicker; hence, dermatologists should obtain a full medical history of the patients to make correct diagnoses. It is vital to encourage an exact identification of the etiological agent according to the internal transcribed spacer sequencing in some uncertain cases. This review highlights the importance of mycological tests and fast diagnosis of TI, especially in cases of atypical skin lesions, to choose appropriate treatment and avoid the spread of drug-resistant species.


Introduction
ermatophytes are a group of fungi that cause skin infections known as dermatophytosis, ringworm, or tinea [1].Dermatophytes are keratinophilic and keratinolytic fungi that colonize keratinized tissues, like skin, hair, and nails, and invade the stratum cornea of these tissues [1].This group of fungi belongs to the genera Trichophyton, Epidermophyton, Nannizzia, Paraphyton, Lophophyton, Microsporum, and Arthroderma in dermatophytes [2].Susceptibility to dermatophytosis depends on several risk factors, like wet climate and geographical region, contact with animals, underlying diseases, and age.An optimal environment enables some special species to grow.Tinea incognito (TI) is a term first stated by IVE and Marks in 1968 to declare the condition caused by the use of steroids, leading to an atypical presentation of dermatophyte infections [3].The term "tinea atypica" can sometimes be used instead of TI.The term TI is precisely used for drug-stimulated conditions, but atypical tinea appears in immunocompetent individuals who are not using any topical and systemic immunosuppressive drugs [4].However, there is a viewpoint that the phrase "tinea incognito" is grammatically wrong and it is better to use "tinea D Curr Med Mycol, 2023, 9(2): 52-63 53 incognita" instead [5].
The TI is mostly a side effect of abusing topical or systemic corticosteroids.It is usually a diagnostic challenge for dermatologists as this infection does not have the classic presentations and can imitate other illnesses since corticosteroids can mask signs of underlying lesions [6].Immunomodulators, such as calcineurin inhibitors (including tacrolimus and pimecrolimus) or tumor necrosis factor inhibitor treatment [7], can also cause TI, but it is less commonly observed than corticosteroids [8].There are reports of other drugs, such as fumaric acid esters (a drug used as systemic antipsoriatic) that may cause TI [9].The TI cases have had a worldwide increase, and delays in diagnosis and proper treatment may lead to generalized tinea or leave permanent marks on the patient.Topical corticosteroids can disrupt the local immunity system and the infection may become widespread [6].This mechanism starts with the production of lipocortin following the binding of steroids to their cytoplasmic receptors in keratinocytes.Lipocortins disrupt inflammatory mediators and arachidonic acid production and prevent the migration of polymorphonuclear cells.Lipocartin can also increase vasoconstriction and decrease vascular permeability, which leads to edema and erythema reduction [8].The increase in coinfections, TI, and geographic distribution decreases the chance of treatment success, indicating the need for highly efficient diagnostic approaches.The same concern exists regarding the increased incidence of recurrent and hard-to-treat dermatophytosis.

Search strategy
This narrative review was performed using PubMed and Scopus databases.Search terms included "Tinea incognita" and "Atypical dermatophytosis".The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, reviews, and case reports.The search was restricted to articles written in the English language from the beginning of 2006 to Feb. 01, 2023.Moreover, duplicate articles and nonavailable full-text articles were excluded.The extracted data of the search results were retrieved in this study.The morphological patterns, prevalence, sight of infection, and causative agents were also described.

Results and discussion
Based on the findings, the average age of patients was 38.56 years old (age range of 2-89 years old according to Table 1, a total of 672 cases).It should be noted that TI commonly targets adults.Some academic dermatology centers have reported 5-10% new atypical chronic cases every year [5].In 2018, Stringer et al. showed that children make up 35% of TI cases, and T. tonsurans was the most common agent among pediatric TI [12].However, in the present review, 2.82% of the cases were children (19 out of 672), and M. gypseum was the most common causative agent in children followed by T. mentagrophytes.Zoophilic contributing agents are more common in children due to their relationship with household animals; moreover, T. mentagrophytes and M. canis were other common strains in children [13].The prevalence of dermatophyte infections depends on the geographical situation [14].In recent years, during the COVID-19 pandemic, facial masking in children prepared optimal microenvironments of increased temperature, moisture, and friction on the skin, which could increase the chance of dermatophyte infection.There are three cases of pediatric TI, which were misdiagnosed as allergic contact dermatitis during the COVID-19 pandemic [15].

Literature review of the tinea incognita cases
Tinea incognita plaques are more inflamed, less scaly, and with less raised margins, compared to typical tinea infections.Tinea incognita can spread quicker than typical tinea infection [8].In addition, due to the lack of proper immune-system response in TI, there is no typical central clearing in TI, unlike the typical tinea infection.In children, TI may be misdiagnosed with pediatric cutaneous diseases, like atopic dermatitis [12].Figure 2 illustrates the distribution of different patterns of TI according to the present review of articles from the beginning of 2006 to Feb 01, 2023.As revealed in Figure 2, the eczema-like lesion (49.71%, 431 out of 867 cases) was the most common pattern of TI as mentioned in most of the previous studies [1,16].It is followed by  2).According to Figure 2, rare forms of TI include Zosterlike [14], pustular psoriasis, dermatitis herpetiform [17], erythematosus pemphigoid-like [18], subcorneal pustular dermatosis [19], Majocci granuloma [20], Scutula-like lesion and blepharo-ciliaris [4], parapsoriasis [21], syphilis-like [22], and pseudoimbricata [23].Tinea pseudoimbricata or tinea indecisiva [23] is a special subset of TI that mimics tinea imbricata, which is characterized by multiple concentric rings or in other words "ringwithin-a-ring'' lesions [24].However, despite tinea imbricata, Trichophyton concentricum is not its causative agent.The most common species in tinea pseudoimbricata are T. mentagrophytes complex, followed by T. tonsurans.The rings in tinea pseudoimbricata are the result of fungal invasion and then suppression of local immunity by intermittent usage of immunosuppressive drugs [25].Zoophilic and rare causative agents usually are responsible for rare clinical forms of TI, like T. mentagrophytes [14], M. audouinii var langeronii [19], T. erinacei [20], T. Schoenleinii [21].More usual patterns include Eczemalike, allergy-like [26], and rosacea-like patterns [27].
Considering the exception of an improper immune system, T. rubrum usually causes mild lesions with little inflammation and slight symptoms, which makes it easier to be misdiagnosed.The most common presentation of TI caused by T. rubrum is the eczema-like presentation [1,16], even though there are cases with pustular inflammatory skin lesions [28] and more extensive infections caused by T. rubrum [29].Trichophyton rubrum could invade hair follicles and shafts and make keratinocytes produce interleukin 8 to induce pustules [8].In a review performed in 2017 by Dogra et al., T. rubrum was the contributing agent for the dissimilar infrequent clinical type of TI-like, eczema/psoriasislike, impetigo-like, deep dermal infection/ granuloma, molluscum-like, purpuric tinea corporis, cystic granuloma trichophyticum, tinea pseudo imbricata, bullous lesion, pseudomembranous-like, pustular lesion [4], and nummular scaly papules [30].More extensive cases were reported when they were found to be neglected, especially in zoophilic strains and immunocompromised patients.In case reports of widespread TI, T. mentagrophytes, is commonly the causative agent and these patients are usually under improper treatment with steroids [31,32].Zoophilic strains are more antigenic to humans, usually cause severe inflammatory reactions, and tend to form pustules in comparison with anthropophilic strains [8,14].
The site of infection varies in different regions of the world, possibly due to different occupations and climatic variations [33].According to Dutta et al., the most common site of TI involvement was the face (51%) [34].However, Stringer et al. found that face involvement prevalence was equal to that of truncal involvement.In the present review, it was noticed that 42.85% of the total 882 cases in all studies were tinea corporis followed by tinea facie (30.49%) and tinea cruris (5.10%).Stringer et al. found a relationship between gender and lesion sites; they noticed an association between female gender and facial symptoms and male gender and truncal symptoms [12].

Etiology
According to previous studies, TI was the most common (36%) cutaneous noted adverse drug reaction [35] and the most common reason for using topical corticosteroids (TCs) was undiagnosed tinea (76.7%); other indications include acne, skin lightening, and melasma.[36].Clobetasol propionate and betamethasone topical cream were the most common drugs used alone or in combination with other drugs, such as antifungals and antibacterials [33,36].In a survey about drug adverse effects, 44.21% of complications were related to topical corticosteroids [36].Tinea and TI (13.61%) were not the most common adverse effects in the aforementioned survey, but they were seen objectively among the corticosteroid users.It should be noted that 27.8-87.8% of patients acquired these drugs without a prescription [36][37][38] and usually based on the recommendation of their friends and relatives [38,39].In comparison with other studies, TCs were prescribed for 44-78% of patients by a pharmacist or chemist [34], which had the most prescriptions for tinea-induced corticosteroids [34,37,40,41].Although misdiagnosis of TI by general practitioners (GPs) in 21-27.8% of cases [37,38] and dermatologists in 12.5-40.6% of cases [33,37,42] had partially led to steroid prescription.In a study, most of the TI patients were male (71.5%) [33]; however, in another study, males and females were equally affected (49.7 % male, 50.3% female) [37].In addition, females made up most of the cases (61.9%) in another research [43].It seems that the usage of TCs is not related to education [37] and patients with a high school education or more were the most affected group [33,37].Nevertheless, there may be a relationship between TI and occupation but it is not clear; in a study, housewives (25.3%) and unemployed or retired individuals (20.7%) were the most affected population [16].Conversely, in another research, students (39.5%) and government employees (25.5%) were the most involved groups [33].Tinea incognita can be the result of ringworms, but due to the high prevalence of tinea corporis, TI cases that originated from tinea corporis are more frequent [1].Besides, tinea faciei has the least frequency among dermatophytosis; however, due to the misdiagnosis of tinea faciei, it has the highest chance of turning to TI infection among dermatophytosis [34].According to Romeo et al., 36% of tinea faciei cases are misidentified and do not receive suitable cure, which may lead to TI [44].In tinea incognita faciei, autoinfection from pre-existing tinea of other sites should be considered and mycological diagnosis of different body sites should be performed, especially when T. rubrum is responsible for the infection [45].There are case reports of tinea faciei incognito, which followed pre-existing onychomycosis.Trichophyton rubrum was the causative agent obtained from a case of tinea faciei incognito with a history of onychomycosis of the foot and another with tinea pedis and a history of tinea unguium [45].Several researchers have claimed that tattoo inoculation could be a causative factor in the development of tattoo-associated tinea; however, in some cases, tattoo-associated systemic fungal infection may be coincidental [46].

Diagnosis
As with every medical diagnosis, the first step to an accurate diagnosis of TI is obtaining a clinical history.There are usually common points among TI patients, for instance, they usually use immunosuppressive treatments, the lesions have mainly an eczema-like shape, appear in the face or trunk, and are unresponsive to steroids [8].A mycological examination allows a diagnosis to be made on direct examination and therefore, to start treatment, as culture requires a maximum of 3 weeks in 99% of cases.Powdery, cottony, and granular colonies with a yellowish color on the reverse side and brown pigmentation on the back resemble T. mentagrophytes infection [27,42].Trichophyton rubrum usually forms localized eczemalike lesions, which are mostly diagnosed by KOH mount.Lesions caused by T. mentagrophytes are usually without or with less scale.It is diagnosed by culture and usually needs systemic antifungal therapy due to disseminated disease or follicular involvement [47].Microsporum spp. is zoophilic and tends to form more inflamed and pustular lesions, and systemic antifungal therapy is usually necessary for this group [8].In some cases, KOH direct microscopy may be negative, and biopsy or histopathology can help detect the fungal infection [48].Biopsy and confocal microscopy are indeed diagnostic aids but do not specify the genus or species of the fungus.Dermoscopy has recently been introduced into the clinical examination of TI.It is helpful in clinics, especially in cases with non-glabrous skin, comma, corkscrew, and Morse code-like hairs [49,50].Patchy erythema, dotted vessels with peripheral distribution and scattered telangiectasias, white scales with peripheral distribution, perifollicular casts, and transparent thin hairs with comma and cork-screw and morse-code view were seen in dermoscopy [51,52].Confocal laser scanning microscopy (CLSM) is a noninvasive method, which facilitates the visual detection of superficial fungal hyphae and spores.The CLSM produces high-resolution imaging by reflectance confocal microscopy (RCM) or immunofluorescence following laser illumination of the tissue.Wavelength used in device reports; RCM (830 nm), infrared CLSM (1064 nm), and dual RCM/CLSM (488 nm and 785 nm) [53].The RCM could visualize fungal hyphae and spores [54], but it is unable to differentiate fungal species.Therefore, fungal culture remains mandatory in cases where species identification is important for diagnostic or therapeutic purposes [55].The tinea diagnosis method is still controversial, but generally, advanced tests (like a biopsy, histopathology, and mycological examination) are recommended when an old skin disease appears with a new face.In some cases, KOH direct microscopy may be negative, and biopsy and histopathology can help see the fungal infection [48].In addition to conventional dermatophyte diagnostics, i.e. direct microscopy and cultivation with subsequent morphological differentiation, molecular methods are becoming increasingly important.It has been declared in several studies that the polymerase chain reaction (PCR) method is more sensitive than cultures.Moreover, in some samples, like nails, skin, and hair, it is rarely possible to be cultivated which may lead to false negative results [56].Besides this, culture takes at least 4 weeks to display the result, which may lead to misdiagnosis in this period.In addition, PCR is able to detect dead cells as well as dormant cells, which are unable to be cultured due to their silent division activity [57].
Although there are subjects that need to be proven about the PCR method, it is considered a reasonable method in treatment control [57].In PCR, ribosomal genes, such as 18S rDNA and internal transcribed spacer 2 (ITS2) and ITS1 are used in fungal differentiation.The ITS region is preferred in dermatophytes due to the high phylogenic similarity in other regions.There are a few more genes, which are used besides ITS, including chitinase-1 (CHS1), topoisomerase-2 (TOP2), β-tubulin (BTU), or translation elongation factor 1-α (EF-1-α).
Researchers have analyzed the CHS1 gene in different dermatophyte species with different results in the sequences [58][59][60], but except for T. rubrum and T. violaceum, none of the closely related species' groups have been analyzed [9].Hence, the CHS1 gene is recommended for the detection of dermatophytes in nail, hair, and skin samples by some scientists [61][62][63].
Similarly, the TOP2 gene can be used for dermatophyte detection, but it cannot differentiate between the T. mentagrophytes species complex isolates [64].
The BTU gene is barely used instead of ITS despite its diversity in Microsporum, since the Trichophyton Species are less diverse as there are no differences between T. benhamiae and T. concentricum, and only one SNP (single nucleotide polymorphisms) between T. Schoenleinii and T. quinckeanum and two SNP between T. rubrum and T. violaceum [65].Recently, the EF1-α gene has been introduced as an identification gene sequence as precise as ITS in dermatophytes detection.
In some species, such as T. tonsurans and T. equinum or M. canis and M. ferrugineum EF1-α gene is more specific and useful.[66,67].Molecular methods, like PCR and matrix-assisted laser desorption ionization: time of flight/mass spectrometry (MALDI-TOF-MS) are gaining more importance along with usual dermatophyte diagnostics.The MALDI-TOF-MS is based on the analysis of ionized fragments of biomolecules like peptides, lipids, and saccharides [57].Table 2 defines every method for facing dermatophytosis.

Treatment
As it was mentioned before, since the most common cause of TI is corticosteroid abuse followed by misdiagnosis and improper treatment, the most important step in TI treatment is ceasing the corticosteroids.The next steps depend on the overall situation of the patient to prescribe the most suitable antifungal treatment.In recalcitrant cases, systemic The conventional method to identify fungi is time-consuming (it takes weeks and may lead to delay in treatment ) and dependent on the vitality of fungi [80].Culture is the gold standard for the diagnosis of dermatophytosis [55].antifungals are prescribed the same as in hair and nail involvement systemically and topically; Usually terbinafine or itraconazole along with clotrimazole is prescribed [47].Nowadays due to the new emerging terbinafine-resistance isolates, specialists prefer to prescribe azoles instead of terbinafine including itraconazole [68] or voriconazole [69].

Conclusion
Based on the review of the literature, a corticosteroid may cause different clinical manifestations of dermatophytes that might be very different from those that are commonly described.Dermatophytosis is a highly communicable disease and there is a concern about the transmission of antifungal-resistant species.Consequently, dermatologists should obtain the full medical history of the patients to make correct diagnoses.It is also of great importance to encourage an exact identification of the etiological agent in some uncertain cases.
To conclude, the prescription of topical/oral corticosteroids should still be limited and done with caution until confirmation of diagnosis, particularly considering the use of steroids during the COVID-19 pandemic.Furthermore, the knowledge of skilled mycologists can play a key role and make a difference in changing the scientific community.This review highlighted the importance of mycological tests in the case of atypical skin lesions to choose appropriate treatment and avoid the spread of drug-resistant species.

Figure 1 -
Figure 1-Causative agents of Tinea incognita in previous studies

Figure 2 -
Figure 2-Different patterns of tinea incognita from 2006 to 2023

9
Genetic methods (polymerase chain reaction-based analyses) Organism detection Fast technique to detect and identify even non-vital fungi; awaits standardization; special equipment needed 10 Matrix-assisted laser desorption ionization-time-of-flight analysis Organism detection Fast technique to identify cultured fungi; based on organism fragments detection; awaits standardization; sophisticated equipment needed Curr Med Mycol, 2023, 9(2): 52-63 61

Table 1 .
Anatomical site distribution, different patterns of tinea incognita and etiological agents.